Download Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil

Eur Respir J 2006; 28: 1195–1203
DOI: 10.1183/09031936.06.00044406
CopyrightßERS Journals Ltd 2006
Long-term outcome in pulmonary arterial
hypertension patients treated with
subcutaneous treprostinil
R.J. Barst*, N. Galie#, R. Naeije", G. Simonneau+, R. Jeffs1, C. Arneson1 and L.J. Rubine
ABSTRACT: Pulmonary arterial hypertension (PAH) is fatal if untreated. Intravenous
epoprostenol improves exercise capacity and haemodynamics in PAH, and increases survival
in idiopathic PAH (IPAH). To evaluate the effects of subcutaneous (SC) treprostinil, a longeracting prostacyclin analogue, followed by the addition of other PAH therapies if needed, 860 PAH
patients treated with SC treprostinil for up to 4 yrs were followed.
Survival is reported as Kaplan–Meier estimates. For 332 IPAH patients with baseline
haemodynamics, observed survival is also compared with predicted survival using the National
Institute of Health formula.
Out of the 860 patients, 199 (23%) discontinued due to adverse events, 136 (16%) died, 117
(14%) discontinued due to deterioration, 29 (3%) withdrew consent and 11 (1%) underwent
transplantation. In total, 97 patients (11%) switched from SC treprostinil to an alternative
prostacyclin analogue; bosentan was added in 105 patients (12%) and sildenafil in 25 (3%).
In conclusion, survival was 87–68% over 1–4 yrs for all 860 patients and 88–70% over 1–4 yrs
with subcutaneous treprostinil monotherapy. For the idiopathic pulmonary arterial hypertension
subset with baseline haemodynamics (n5332), survival was 91–72% over 1–4 yrs. In contrast,
predicted survival was 69–38% over 1–4 yrs. The safety profile for long-term subcutaneous
treprostinil was consistent with previous short-term trials with no unexpected adverse events.
KEYWORDS: Idiopathic pulmonary arterial hypertension, prostacyclin analogue, pulmonary
arterial hypertension, survival, treprostinil
ulmonary arterial hypertension (PAH) is a
disease that leads to a progressive
increase in pulmonary vascular resistance
and right heart failure [1, 2]. In 1980, the National
Institute of Health established an idiopathic PAH
(IPAH) registry (previously termed primary
pulmonary hypertension), which described the
characteristics of IPAH and its natural history
over a 5-yr period. The median survival was
2.8 yrs, with survival rates of 68, 48, and 34% at 1,
3 and 5 yrs, respectively [3]. Despite therapeutic
advances, PAH remains a life-threatening disorder without a cure. In 1995, i.v. epoprostenol
was approved by the Food and Drug Association
for the treatment of severe IPAH, and was
subsequently approved in 2000 for PAH related
to the scleroderma spectrum of disease [4, 5]. The
first oral therapy, bosentan, an endothelin receptor antagonist, was approved in 2001 [6] and the
P
prostacyclin analogue treprostinil was approved
for continuous subcutaneous (SC) infusion in
2002 [7]. In 2004, the prostacyclin analogue
iloprost was approved via inhalation [8], and in
2005 the oral phosphodiesterase inhibitor sildenafil was approved [9].
CORRESPONDENCE
R.J. Barst
Columbia University College of
Physicians and Surgeons
3959 Broadway
BHN 2-255
New York
NY 10032
USA
Fax: 1 2123421443
E-mail: [email protected]
Received:
March 30 2006
Accepted after revision:
July 25 2006
Treprostinil is a prostacyclin analogue that
possesses similar pharmacological actions to
epoprostenol, including vasodilatation of pulmonary and systemic arterial vascular beds and
inhibition of platelet aggregation [10, 11].
However, epoprostenol therapy is associated
with problems due to its short half-life (3–
6 min) [12], necessitating continuous i.v. infusion
via a central venous catheter. Treprostinil, unlike
epoprostenol, is stable at room temperature and
has a neutral pH with an elimination half-life of
4.5 h (with a distribution half-life of approximately
For editorial comments see page 1073.
This article has supplementary material accessible from www.erj.ersjournals.com
EUROPEAN RESPIRATORY JOURNAL
AFFILIATIONS
*Columbia University College of
Physicians and Surgeons, New York,
NY,
1
United Therapeutics Corporation,
Research Triangle Park, NC, and,
e
University of California, San Diego,
School of Medicine, La Jolla, CA,
USA.
#
Institute of Cardiology, University of
Bologna, Bologna, Italy.
"
Erasmus University Hospital,
Brussels, Belgium, and
+
Hospital Antoine Beclere, Clamart,
France.
VOLUME 28 NUMBER 6
European Respiratory Journal
Print ISSN 0903-1936
Online ISSN 1399-3003
c
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LONG-TERM SUBCUTANEOUS TREPROSTINIL THERAPY
40 min) [13]. These properties permit the delivery of
treprostinil via SC infusion. However, SC treprostinil therapy
can be limited by pain at the SC infusion site.
A placebo-controlled pilot study, evaluating the safety and
efficacy of SC treprostinil infusion in 26 PAH patients [13],
found favourable trends in exercise capacity, dyspnoea and
haemodynamics. Subsequently, two double-blind, randomised, placebo-controlled 12-week studies in a total of 470
patients demonstrated that SC treprostinil therapy improves
exercise capacity and haemodynamics [7]. Patients who
participated in these controlled studies were eligible to enrol
in an open-label extension study. In addition, de novo patients
were also eligible to enrol in the open-label study. Subjects
who participated in these studies received SC treprostinil
therapy for up to 4 yrs. The objectives of the present open-label
study were to retrospectively analyse the effects of SC
treprostinil monotherapy (as well as SC treprostinil therapy
with the addition of other PAH therapies if needed) on
outcomes in PAH. In a subset of patients with IPAH in whom
baseline haemodynamic measurements were available, the
current authors also compared observed survival with predicted
survival, determined using the formula by D’ALONZO et al. [3]
based on the National Institute of Health (NIH) Registry data.
METHODS
Patients
Patients evaluated in these analyses were enrolled in the three
placebo-controlled trials of SC treprostinil in PAH [7, 13]. De
novo patients were also eligible if they met the following entry
criteria: 1) New York Heart Association (NYHA) functional
class II, III or IV; 2) PAH, either idiopathic or associated with
connective tissue disease; 3) congenital heart disease; 4) portal
hypertension; or 5) HIV. Additional entry criteria included: 1)
aged o8 yrs; 2) mean pulmonary artery pressure o25 mmHg;
3) mean pulmonary capillary wedge pressure f15 mmHg; 4)
pulmonary vascular resistance .3 units (measured or calculated by right heart catheterisation); and 5) 6-min walk distance
50–450 m. Patients had no previous exposure to prostaglandins or their analogues. Background PAH therapies, e.g. anticoagulants, oral vasodilators, cardiac glycosides, diuretics and
supplemental oxygen, were administered at the discretion of
the treating physicians. Treprostinil was administered as a
continuous SC infusion via an ambulatory micro-infusion pump.
Patients randomised to treprostinil in a prior controlled study
continued receiving treprostinil at the same dose they were
receiving at the end of the prior study, with subsequent dose
adjustments based on investigator discretion. Patients receiving
placebo in previous controlled studies and de novo patients
started treprostinil at a dose of 1.25 ng?kg-1?min-1 with dose
increases based on PAH signs and symptoms, and side effects.
All studies were conducted in accordance with the Amended
Declaration of Helsinki in the North America, Europe,
Australia and Israel sites. Studies were approved by local ethics
review committees. Written informed consent (and assent as
indicated) was obtained from all patients (and/or parents).
In addition to treatment with chronic SC treprostinil, the use of
additional PAH treatments was at the discretion of the treating
physicians. Patients continued in the study until one of the
following: 1) death; 2) transplantation; 3) initiation of i.v.
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VOLUME 28 NUMBER 6
R.J. BARST ET AL.
inhaled or oral prostaglandins or their analogues; or 4) an
intolerable adverse event (AE).
Data on vital status, safety and additional or alternative
treatments were collected from June 25, 1998 to December 1,
2003 (data cut-off).
Statistical analyses
Baseline parameters were recorded at the start of treprostinil
treatment. Survival was assessed from the start of treprostinil
to death or data cut-off. All treprostinil-treated PAH patients
were included in the analyses (intent to treat). The Kaplan–
Meier method was used to estimate the proportion of patients
surviving at each time point. The date of initial treprostinil
dosing was used as the index date for determining survival.
Patients were censored if they underwent transplantation or
discontinued treprostinil. Survival rates were also estimated
for patients treated with SC treprostinil monotherapy, censoring patients when additional PAH treatment was added. A
separate analysis of survival was performed for the subgroup
of patients with IPAH with available baseline haemodynamics.
Expected survival was calculated for each IPAH patient based
on the NIH formula [3]. Possible predictors of survival were
tested using a proportional hazards model. All variables were
fit simultaneously to estimate hazard ratios. Sensitivity
analyses were carried out to determine whether patients who
discontinued due to AEs differed from the remainder of the
cohort with respect to baseline demographic and clinical
characteristics, including known PAH risk factors, e.g. PAH
aetiology, NYHA class, haemodynamic parameters, or the time
from diagnosis to the initiation of SC treprostinil therapy.
Safety was evaluated by AEs and laboratory values.
Laboratory values were summarised descriptively at baseline
and every 6 months thereafter. Baseline was defined as the
measurement just prior to the first dose of treprostinil in either
the controlled studies or open-label study. AEs were recorded
throughout the study. An AE was considered ‘‘treatment
emergent’’ if it first occurred or worsened following treprostinil initiation, and ‘‘treatment related’’ if it was considered by
the investigator to be possibly or reasonably attributable to
treprostinil treatment.
RESULTS
Patient population
In total, 860 patients were included in the analyses. Of these:
653 (76%) patients were female; 711 (83%) were Caucasian; 63
(7%) were Hispanic; 48 (6%) were of African origin; 23 (3%)
were Asian; 11 (1%) were other of races; and four (,1%) were
Native American. The mean (range) age was 46 (5–84) yrs. In
total, 32 (4%) patients were f16 yrs of age and 21 (2%) patients
were o75 yrs of age.
PAH history at time of enrolment for the 860 patients is
summarised in table 1. The initial PAH diagnosis was made an
average of 42 months before enrolment. The most common
diagnosis for the 860 patients was IPAH (48%; n5412). In total,
13 (2%) patients were HIV positive, with HIV status being
unknown for an additional 41 (5%) patients. Patients had been
at their current NYHA class for a mean 15 months before
enrolment. The majority of patients were NYHA class III (76%;
n5654) at baseline.
EUROPEAN RESPIRATORY JOURNAL
R.J. BARST ET AL.
TABLE 1
LONG-TERM SUBCUTANEOUS TREPROSTINIL THERAPY
Pulmonary arterial hypertension history
Subjects n
860
IPAH
412 (48)
IPAH associated with
Congenital systemic to pulmonary shunts
177 (21)
Diffuse cutaneous systemic sclerosis
72 (8)
Thromboembolic disease
49 (6)
Portopulmonary hypertension
43 (5)
Systemic lupus erythematosus
35 (4)
Limited cutaneous systemic sclerosis
28 (3)
Mixed connective tissue disease
27 (3)
HIV
13 (2)
Overlap syndrome
4 (,1)
Months since diagnosis
42¡74
HIV
No
806 (93)
Yes
13 (2)
Unknown
41 (5)
NYHA functional class at baseline
II
128 (15)
III
654 (76)
IV
78 (9)
Months at baseline NYHA functional class
15¡31
Data are presented as n (%) or mean¡SD, unless otherwise stated. IPAH:
idiopathic pulmonary arterial hypertension; NYHA: New York Heart Association.
TABLE 2
Patient disposition
Subjects
Total in previous controlled study
860
205
Randomised to receive placebo in previous study
218
437 (51)
Completed#
331 (38)
Prematurely discontinued
506 (59)
Ongoing as of December 1, 2003
23 (3)
Reason for premature discontinuation
Death
Transplantation
Clinical deterioration/rescue therapy
Withdrew consent
Adverse event
136 (16; 27)
11 (1; 2)
117 (14; 23)
29 (3; 6)
199 (23; 39)
Protocol violation
10 (1; 2)
Lost to follow-up
4 (,1; 1)
Data are presented as n, n (%) or n (% total; % discontinuations). #: transitioned
to commercial drug.
Patient disposition
Patient disposition is summarised in table 2. In total, 860
patients were treated with SC treprostinil, including 423 (49%)
who entered from controlled clinical studies and 437 (51%) de
novo patients. Of the 423 patients who had previously
participated in a controlled clinical study, 205 patients had
received treprostinil and 218 patients had received placebo.
EUROPEAN RESPIRATORY JOURNAL
Concomitant PAH medications
While all patients were started on SC treprostinil as PAH
monotherapy, the addition of other PAH treatments was at the
discretion of the treating physician. In total, 98 patients were
started on alternative prostacyclin analogues during the study,
i.e. i.v. epoprostenol (n584), inhaled iloprost (n58) and oral
beraprost (n56). Of these, 97 patients were transitioned off SC
treprostinil to the alternative prostacyclin analogue and one
patient had inhaled iloprost added during the study. However,
it was discontinued after 8 days. In addition, during the study,
bosentan was initiated in 12% (105 out of 860) of patients and
sildenafil was added in an additional 3% (25 out of 860) of
patients. None of the patients were treated with both bosentan
and sildenafil in addition to SC treprostinil.
423 (49)
Randomised to receive treprostinil in previous study
De novo patients
As of December 1, 2003, 354 (41%) of the 860 treated patients
had remained on treprostinil and 506 (59%) had discontinued
(table 2). The mean¡SD duration of exposure for the 354
patients was 135¡41 weeks. Out of the 860 treated patients,
23% (199 out of 860) discontinued due to AEs, 16% (136 out of
860) died, 14% (117 out of 860) discontinued due to deterioration, 3% (29 out of 860) withdrew consent, 1% (11 out of 860)
underwent transplantation, 1% (10 out of 860) were withdrawn
due to a protocol violation, and ,1% (four out of 860) were lost
due to follow-up. The 199 AEs that led to discontinuation were
predominantly related to the study drug, i.e. infusion site pain
and/or reaction (n5196). However, the dropout rate for site
pain (fig. 1) demonstrates that if the patient discontinued
treatment with SC treprostinil due to site pain, it was most
likely to occur during the first year of treatment (fig. 2). In
addition, sensitivity analyses did not demonstrate any significant differences between the patients who dropped out due
to site pain versus those who did not.
Duration of exposure and changes in mean doses over time
Continuous SC treprostinil was administered to 538 (63%)
patients, 312 (36%) patients, 135 (17%) patients and 13 (2%)
patients for 1, 2, 3 and 4 yrs respectively. As of December 1,
2003, 860 patients had received treprostinil for a total of 1,419
patient-yrs, with exposure of up to 4.5 yrs. The average dose
increased from 1.25 ng?kg-1?min-1 at initiation to 26, 36, 42 and
42 ng?kg-1?min-1 at 1, 2, 3 and 4 yrs, respectively.
Survival analyses
Kaplan–Meier survival rates for the 860 treated patients,
including 412 with IPAH and 448 with PAH related to other
conditions, were 87, 78, 71 and 68% at 1, 2, 3 and 4 yrs,
respectively (fig. 3). Survival rates with SC treprostinil monotherapy, censoring patients when additional targeted PAH
therapy was added (130 out of 860 patients, i.e. 15% of the total
cohort received additional PAH treatment), were 88, 79, 73 and
70% at 1, 2, 3 and 4 yrs, respectively (fig. 4), and not
significantly different than for the entire cohort. In addition,
due to the significant drop-out rate due to site pain during the
first year of treatment, survival rates were estimated for
patients treated with SC treprostinil for o1 yr. Survival rates
90, 82 and 79% at 2, 3 and 4 yrs, respectively (fig. 5).
Out of the 412 IPAH patients, baseline haemodynamics were
available for 332 patients as follows: mean pulmonary artery
pressure 59¡13 mmHg; mean right atrial pressure
VOLUME 28 NUMBER 6
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LONG-TERM SUBCUTANEOUS TREPROSTINIL THERAPY
R.J. BARST ET AL.
90
90
80
80
Site pain dropout %
100
Site pain dropout %
100
70
60
50
40
30
70
60
50
40
30
20
20
10
10
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0
0.0
4.5
0.5
1.0
1.5
Time yrs
FIGURE 1.
2.0
2.5
3.0
3.5
4.0
4.5
Time yrs
Kaplan–Meier time to discontinuation due to site pain in 860
FIGURE 2.
Kaplan–Meier estimate of time to discontinuation due to site pain in
subcutaneous treprostinil-treated pulmonary arterial hypertension patients.
196 patients who discontinued subcutaneous treprostinil. The time to discontinua-
Discontinuation estimates (95% confidence intervals) were 83% (81–86) at 1 yr,
tion estimates (95% confidence intervals) were 34% (27–40) at 1 yr, 9% (6–14) at 2
75% (72–78) at 2 yrs, 70% (66–74) at 3 yrs and 67% (62–72) at 4 yrs. The number
yrs and 1.5% (0.4–4) at 3 yrs. The numbers of patients at risk were 66, 18, 3 and 0 at
patients at risk were 538, 312, 135 and 13 at 1, 2, 3 and 4 yrs, respectively.
1, 2, 3 and 4 yrs, respectively.
10¡5 mmHg; and cardiac index 2.2¡0.7 L?min-1?m-2. Baseline
clinical characteristics and demographics for these 332 IPAH
patients are shown in table 3. Observed survival rates for the
332 IPAH patients were 91, 82, 76 and 72% at 1, 2, 3 and 4 yrs,
respectively. In contrast, expected survival rates (calculated for
each patient based on the NIH formula) were 69, 56, 46, and
38% at 1, 2, 3 and 4 yrs, respectively (fig. 6).
Predictors of survival
Complete baseline demographic and clinical characteristics
and haemodynamics were available in 432 PAH patients.
Although the associations of both mixed venous oxygen
saturation and pulmonary vascular resistance with survival
were statistically significant (p50.01, hazard ratio (95%
confidence) 0.98 (0.96–0.99); and p50.04, 1.03 (1.002–1.05),
respectively), the magnitude of these associations was small.
However, in the IPAH subset (baseline parameters available in
265 patients), the association between NYHA class and
survival was significant statistically and in magnitude
(NYHA class IV versus NYHA class III p50.001, 5.35 (1.96–
14.56); and NYHA class IV versus NYHA class II p50.002, 8.74
(2.23–34.21)).
Survival rates were highest for NYHA class II patients (n5128)
at study entry, with survival rates of 91, 84, 79 and 74% at 1, 2,
3 and 4 yrs, respectively. Survival rates for NYHA class III
patients (n5654) were 88, 79, 72 and 70% at 1, 2, 3 and 4 yrs,
respectively; while survival rates for NYHA class IV patients
(n578) were 71, 62 and 52% at 1, 2 and 3 yrs, respectively (fig. 7).
90
90
80
80
70
70
60
Survival %
Survival %
100
100
60
50
50
40
40
30
30
20
20
10
10
0
0.0
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Time yrs
Time yrs
FIGURE 4.
FIGURE 3.
Observed survival with subcutaneous treprostinil monotherapy.
Observed survival in 860 subcutaneous treprostinil-treated
Patients were censored when additional pulmonary arterial hypertension therapies
pulmonary arterial hypertension patients. Survival estimates (95% confidence
were initiated. Survival estimates (95% confidence intervals) were 88% (85–90) at 1
intervals) were 87% (84–89) at 1 yr, 78% (75–81) at 2 yrs, 71% (67–75) at 3 yrs and
yr, 79% (76–82) at 2 yrs, 73% (69–77) at 3 yrs and 70% (64–74) at 4 yrs. The
68% (63–73) at 4 yrs. The numbers of patients at risk were 538, 312, 135 and 13 at
numbers of patients at risk were 859, 525, 298, 118 and 11 at 0, 1, 2, 3 and 4 yrs,
1, 2, 3, and 4 yrs, respectively.
respectively.
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R.J. BARST ET AL.
LONG-TERM SUBCUTANEOUS TREPROSTINIL THERAPY
100
Baseline demographics and clinical
characteristics in idiopathic pulmonary arterial
hypertension patients#
TABLE 3
90
Survival %
80
70
Subjects
332
60
Age yrs
45¡15
Sex
50
40
Male
74 (22)
Female
258 (78)
30
Months from diagnosis
20
NYHA functional class at baseline
10
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Time yrs
28¡45
II
53 (16)
III
262 (79)
IV
17 (5)
Months at baseline NYHA functional class
13¡21
Ppa mmHg
59¡13
Pra mmHg
FIGURE 5.
Observed survival for 538 patients who were treated with
10¡5
CI L?min-1?m-2
2.2¡0.7
subcutaneous treprostinil for o1 yr. Survival estimates (95% confidence intervals)
were 90% (86–92) at 2 yrs, 82% (77–86) at 3 yrs and 79% (73–83) at 4 yrs. The
Data are presented as n, mean¡SD or n (%). NYHA: New York Heart
numbers of patients at risk were 538, 312, 135 and 13 at 1, 2, 3 and 4 yrs,
Association; Ppa: mean pulmonary artery pressure; Pra: mean right atrial
respectively.
pressure; CI: cardiac index.
#
: idiopathic pulmonary arterial hypertension
patients with baseline haemodynamic parameters.
Adverse events
A total of 168 patients died during the study or within 30 days
of study discontinuation. One death was attributed to
treprostinil by the investigator. The cause of this death was
reported as progressive PAH. The patient had been receiving
treprostinil for 1,123 days and was receiving 45 ng?kg-1?min-1
at the time of death.
A total of 415 patients had at least one serious AE, with 62 (7%)
having a serious AE attributable to treprostinil. Overall, the
reported serious AEs were typical of patients with PAH and
included heart failure (14%; n5122), pulmonary hypertension
(9%; n576), syncope (4%; n538), pneumonia (4%; n537) and
dyspnoea (3%; n528). Serious AEs attributable to treprostinil
included site infection (n59), systemic hypotension (n58), site
pain (n57), dyspnoea (n54), syncope (n54) and heart failure
(n54).
The AEs experienced by the study patients are shown in
table 4. The most frequently reported AEs were infusion site
pain in 792 (92%) patients and site reaction in 700 (81%)
patients. Infusion site reactions were defined as any local AE
other than pain, bleeding or bruising at the infusion site and
were most often erythema, swelling, induration or rash. There
were no reported episodes of catheter-related sepsis. Other less
frequently observed treatment-related site events were bleeding/bruising in 170 (20%) patients and infection in 35 (4%)
patients.
Treatment-related events leading to a dose reduction in o1%
of patients were: diarrhoea (6.6%; n557); headache (6.3%;
n554); nausea (6.2%; n553); vomiting (2.7%; n523); pain
(2.4%; n521); vasodilatation (2.4%; n521); dizziness (2.3%;
n520); jaw pain (1.7%; n515); systemic hypotension (1.6%;
n514); and anorexia (1.0%; n59).
All treatment-emergent AEs reported in o10% of the 860
patients were well-characterised side effects of prostacyclin
and its analogues, e.g. diarrhoea (42%; n5365), nausea (27%;
100
90
80
Survival %
Clinical laboratory values
All mean chemistry, haematology, coagulation and urinalysis
values were within normal ranges throughout the 4 yrs of
treatment.
70
60
50
40
30
20
10
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Time yrs
FIGURE 6.
Observed survival (–––) in 332 subcutaneous treprostinil-treated
IPAH patients (with baseline haemodynamic parameters available) versus predicted
The treatment-related events rated as severe in intensity for
o1% of patients were: headache (1.7%; n515); pain (1.4%;
n512); diarrhoea (1.3%; n511); and nausea (1.2%; n510).
Headache was the only treatment-related AE, other than site
events, that led to discontinuation for five (0.6%) patients.
survival (- - -) by the National Institute of Health equation. Survival estimates (95%
EUROPEAN RESPIRATORY JOURNAL
VOLUME 28 NUMBER 6
confidence intervals) were 91% (87–94) at 1 yr, 82% (76–86) at 2 yrs, 76% (69–81) at
3 yrs and 72% (65–78) at 4 yrs versus predicted survival rates of 69, 56, 46 and 38%
at 1, 2, 3 and 4 yrs, respectively. The numbers of patients at risk were 231, 149, 82
and 10 at 1, 2, 3 and 4 yrs, respectively.
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LONG-TERM SUBCUTANEOUS TREPROSTINIL THERAPY
R.J. BARST ET AL.
100
hospitalisation and two (0.2%) reporting thrombocytopaenia
as a severe event; all events resolved. One out of the six
patients had PAH associated with portopulmonary hypertension. This patient reported a single, mild episode of thrombocytopaenia, which resolved in 31 days.
90
80
Survival %
70
60
Renal (n512) and hepatic failure (n53) were infrequent and
appeared not to be associated with treprostinil.
50
40
30
20
10
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Time yrs
FIGURE 7.
Observed survival in 860 subcutaneous treprostinil-treated
pulmonary arterial hypertension patients, based on the New York Heart
Association (NYHA) functional class at time of treprostinil initiation. NYHA class II:
- - -; NYHA class III: ? ? ? ?; NYHA class IV: –––. Survival rates for 128 NYHA class II
patients (95% confidence intervals (CI)) were 91% (84–95), 84% (75–90), 79% (68–
86) and 74% (62–83) at 1, 2, 3 and 4 yrs, respectively. Survival rates for 654 NYHA
class III patients (95% CI) were 88% (85–91), 79% (75–82), 72% (67–76) and 70%
(64–75) at 1, 2, 3 and 4 yrs, respectively. Survival rates for 78 NYHA class IV patients
(95% CI) were 71% (58–81), 62% (48–73) and 52% (36–66) at 1, 2 and 3 yrs,
respectively. The number of patients at risk in NYHA class II was 91, 59, 34, and 5 at
1, 2, 3 and 4 yrs, respectively; NYHA class III was 409, 230, 96 and 8 at 1, 2, 3 and 4
yrs, respectively; and NYHA class IV was 38, 23, 2 and 0 at 1, 2, 3 and 4 yrs,
respectively.
n5235), headache (25%; n5214), jaw pain (23%; n5195), pain
(16%; n5139), vasodilatation (13%; n5115), anorexia (10%;
n589) and rash (10%; n588).
Delivery system complications were reported in 255 (30%) out
of the 860 patients. These complications were most often due to
pump malfunction, which was reported in 222 (26%) out of the
860 patients, or infusion set complications which were
reported in 74 (9%) of the study patients. Pump failures were
managed by correcting the alarm condition and/or substituting the backup pump, with no reported incidences of clinically
significant deterioration occurring in association with the drug
delivery system malfunction.
Overdoses were reported due to programming errors (n53),
accidental bolus infusions (n54), concentration increases
without rate decreases (n56), and infusion set replacement
following catheter dislodgement (n51).
Haemorrhagic events not related to the infusion site were
epistaxis (2%), ecchymosis (1%), haemoptysis (1%) and
haemorrhage (,1%). These events did not appear to be related
to the treprostinil dose. One patient was hospitalised for
gastrointestinal haemorrhage and one patient for epistaxis.
Both of these events resolved without sequelae. These were the
only haemorrhagic events rated as severe in intensity. The
gastrointestinal haemorrhage was the only haemorrhagic event
leading to discontinuation.
Thrombocytopaenia was reported as a treatment-related event
in six (0.7%) patients with one (0.1%) patient requiring
1200
VOLUME 28 NUMBER 6
DISCUSSION
In the present study, the observed survival rates over 1–4 yrs
were 87–68% for the entire cohort of 860 PAH patients treated
with SC treprostinil. Survival rates with SC treprostinil
monotherapy were 88–70% over 1–4 yrs, which is not
significantly different than for the entire cohort, or for the
cohort of patients excluding those who received combination
therapy, in whom survival rates were 84–63% over 1–4 yrs
(data not shown). For the IPAH patients, observed survival
rates over 1–4 yrs were 91–72% compared with predicted
survival rates of 69–38% [3]. Survival was also evaluated in this
study by NYHA class at treatment initiation. This analysis was
performed because poor survival has been associated with
NYHA class in various studies, e.g. IPAH patients from the
NIH Registry, IPAH patients treated with i.v. epoprostenol,
and IPAH patients treated with oral bosentan [3, 14–16].
Historically, survival for NYHA class III and IV patients from
the NIH Registry was 32 and 6 months, respectively [3]. The
results of the present study were consistent with the NIH
Registry with improved survival rates for patients who were
NYHA class II (n5128) at study entry (observed survival was
91, 84, 79 and 74% at 1, 2, 3 and 4 yrs, respectively) versus
NYHA class III (88, 79, 72 and 71% at 1, 2, 3 and 4 yrs,
respectively; n5654) or NYHA class IV (71, 62 and 52% at 1, 2
and 3 yrs, respectively; n578).
Observational studies have demonstrated a survival benefit in
IPAH with warfarin [17, 18], and with chronic calcium-channel
blockers in the small subset of IPAH patients who demonstrate
acute pulmonary vasoreactivity [19]. In the 12-week randomised open-label trial of 81 NYHA class III and IV IPAH
patients, survival was improved in patients treated with i.v.
epoprostenol compared with patients treated with conventional therapy alone [4]. Since that study, several observational
studies have confirmed a long-term survival benefit in NYHA
class III and IV IPAH patients treated with i.v. epoprostenol
when compared with either historical controls or predicted
survival based on the NIH Registry equation [14, 15]. In a
recently published review from 1992–2002, survival rates were
reported for IPAH patients treated with conventional therapy
alone versus i.v. epoprostenol plus conventional medical
therapy. The 1, 2 and 3 yr survival rates were 72, 53 and
48%, respectively, for patients who did not receive i.v.
epoprostenol versus 82, 74 and 62%, respectively, for patients
who did receive i.v. epoprostenol [2]. The observed and
predicted survival rates from the observational epoprostenol
studies are similar to the observed and predicted survival rates
for the IPAH patients in the present study. However, lifethreatening AEs associated with i.v. epoprostenol, such as
sepsis and drug interruption, are unlikely to occur with SC
treprostinil.
EUROPEAN RESPIRATORY JOURNAL
R.J. BARST ET AL.
TABLE 4
LONG-TERM SUBCUTANEOUS TREPROSTINIL THERAPY
Adverse events
Subjects
Serious adverse events
Heart failure
Pulmonary hypertension
Syncope
Pneumnoia
Dyspnoea
Serious adverse events attributable to
treprostinil
Site infection
Systemic hypotension
Site pain
Dyspnoea
Syncope
Heart failure
Adverse events
Infusion site pain
Site reaction
Bleeding/bruising
Infection
Treatment-related events
Headache
Pain
Diarrhoea
Nausea
Treatment-related events leading to dose
reduction
Diarrhoea
Headache
Nausea
Vomiting
Pain
Vasodilatation
Dizziness
Jaw Pain
Systemic hypotension
Anorexia
Prostacyclin-related effects
Diarrhoea
Nausea
Headache
Jaw pain
Pain
Vasodilation
Anorexia
Rash
Delivery system complications
Pump malfunction
Infusion set complications
Overdose
Programming error
Accidental bolus
Concentration increase without rate decrease
Infusion set replacement following catheter
dislodgement
Haemorrhagic events
Epistaxis
Ecchymosis
Haemoptysis
Haemorrhage
Thrombocytopenia
Thrombocytopenia-related hospitalisation
Severe thrombocytopenia
Renal failure
Hepatic failure
Data are presented as n or n (%).
EUROPEAN RESPIRATORY JOURNAL
860
415 (48)
122 (14)
76 (9)
38 (4)
37 (4)
28 (3)
62 (7)
9 (1)
8 (1)
7 (1)
4 (,1)
4 (,1)
4 (,1)
792
700
170
35
(92)
(81)
(20)
(4)
15
12
11
10
(2)
(1)
(1)
(1)
57 (7)
54 (6)
53 (6)
23 (3)
21 (2)
21 (2)
20 (2)
15 (2)
14 (2)
9 (1)
365 (42)
235 (27)
214 (25)
195 (23)
139 (16)
115 (13)
89 (10)
88 (10)
255 (30)
222 (26)
74 (9)
3 (,1)
4 (,1)
6 (1)
1 (,1)
14 (2)
11 (1)
10 (1)
1 (,1)
6 (1)
1 (,1)
2 (,1)
12 (1)
3 (,1)
Subsequently, MCLAUGHLIN et al. [16] reported improved
survival in 169 IPAH patients treated with oral bosentan. The
1, 2 and 3 yr observed survival rates were 96, 89 and 86%,
respectively, compared with NIH predicted survival rates of
69, 57 and 48%, respectively. In addition, survival in IPAH
patients treated with first-line bosentan has been compared
with first-line i.v. epoprostenol [20]. Thus, while these survival
rates are similar to those with SC treprostinil reported in the
present study, clinical trials cannot be directly compared with
each other (table 5).
More recently, PROVENCHER et al. [21] reported that in an IPAH
cohort treated with bosentan, many patients required the
addition of another targeted PAH therapy during long-term
follow-up. In addition, OPITZ et al. [22] also reported the need
to add another PAH therapy in a cohort of IPAH patients
treated with first-line inhaled iloprost. Both studies are not
inconsistent with the observations made in the present study.
In the SC treprostinil 12-week randomised clinical trials,
although 84% of patients receiving the active drug reported
site pain, 27% of patients receiving placebo also reported site
pain. Site pain is a major drawback with SC treprostinil
therapy. In this open-label extension study, 23% of the patients
discontinued due to AEs, with 98% of discontinuations due to
site pain. However, almost 70% of these dropouts occurred
within the first year. For those patients who remained on SC
treprostinil for 1 yr, survival rates were 90–79% at 2–4 yrs. For
the majority of patients, long-term SC treprostinil therapy was
well tolerated in patients who had minimal site pain.
Prostacyclin-related side effects were controlled by dose
adjustment, and no clinically significant changes in laboratory
values were observed. The longer half-life of treprostinil makes
an exacerbation of PAH symptoms resulting from abrupt
cessation of drug less likely to occur with treprostinil than with
epoprostenol. In addition, serious complications associated
with a continuous i.v. infusion, e.g. sepsis or thromboembolic
events, are unlikely to occur with a SC infusion treatment. In
2004, treprostinil was also approved by the Food and Drug
Association for continuous i.v. administration, an alternative
option for patients intolerant to SC treprostinil as well as an
alternative to i.v. epoprostenol. Potential advantages of i.v.
treprostinil over i.v. epoprostenol include better stability, easier
drug preparation and longer duration of activity [23, 24].
There are several important limitations to the current observational study. The use of the NIH Registry equation as opposed
to a parallel placebo-treated or historical control group is a
significant limitation. The NIH equation is based on data from
the 1980s and background practice patterns have changed over
the past 20 yrs. In addition, the 23% discontinuation rate
during the study due to AEs (predominantly site pain) cannot
exclude a selection bias. However, analysing the patients who
dropped out due to site pain versus those who did not, did not
demonstrate any significant differences between the two
groups with respect to known PAH risk factors, such as
NYHA class, PAH aetiology or haemodynamic parameters at
the time of SC treprostinil initiation. Additional limitations in
the present observational study include the doses of treprostinil the patients received were lower than the overall current
doses patients receive. Whether higher doses may have
affected outcome remains to be studied. In addition, with
VOLUME 28 NUMBER 6
1201
c
LONG-TERM SUBCUTANEOUS TREPROSTINIL THERAPY
TABLE 5
R.J. BARST ET AL.
Baseline characteristics of survival and predicted survival in idiopathic pulmonary arterial hypertension patients treated
with i.v. epoprostenol, oral bosentan or subcutaneous (SC) treprostinil based on the National Institute of Health Registry
i.v. epoprostenol#,e
Oral bosentan",##
SC treprostinil+
i.v. epoprostenol1,""
Oral bosentan1,""
Ppa mmHg
61¡13
57¡16
59¡13
59¡15
57¡15
Pra mmHg
14¡6
10¡6
10¡5
10¡5
10¡5
1.8¡0.6
2.4¡0.8
2.2¡0.7
2.1¡0.6
2.2¡0.6
15 (9)
53 (16)
III
75 (46)
139 (82)
262 (79)
83 (100)
83 (100)
IV
87 (54)
15 (9)
17 (5)
88, 59
96, 69
88, 69
93++
95++
80, 56
++
87++
++
CI L?min-1?m-2
NYHA class
I/II
Survival rates yrs
1
2
76, 46
89, 57
89
3
63, 35
86, 48
74, 46
78
82++
4 yrs
56, NA
NA
69, 38
NA
NA
Data are presented as mean¡SD, n (%). For survival rates data are presented as % observed, % predicted, unless otherwise stated. Ppa: mean pulmonary artery pressure;
Pra: mean right atrial pressure; CI: cardiac index; NYHA: New York Heart Association; NA: not available. #: n5162; ": n5169; +: n5332; 1: n583; e: from reference [14];
##
: from reference [16];
""
: from reference [20];
++
: % observed.
either bosentan or sildenafil initiated in 15% of patients, the
current study cannot adequately address the effects of SC
treprostinil monotherapy on survival in PAH.
In conclusion, having multiple therapeutic options available
for pulmonary arterial hypertension patients should improve
the efficacy in treating pulmonary arterial hypertension. The
selection of an ‘‘optimal’’ medical regimen for an individual
patient should be based on a risk–benefit assessment of all
treatment options available. While subcutaneous treprostinil
may not be the drug of first choice for most pulmonary arterial
hypertension patients, having subcutaneous treprostinil as a
therapeutic option may improve outcome in pulmonary
arterial hypertension.
ACKNOWLEDGEMENTS
The authors would like to thank the following investigators for
their contributions. R. Bourge (Birmingham, AL, USA); D. Ross
and S. Shapiro (Los Angeles, CA, USA); R. Channick (San
Diego, CA, USA); T. DeMarco (San Francisco, CA, USA); R.
Doyle (Stanford, CA, USA); R. Oudiz (Torrance, CA, USA); D.
Badesch (Denver, CO, USA); D. Ivy (Denver, CO, USA); C.
Lawrence (Atlanta, GA, USA); S. Rich (Chicago, IL, USA); B.
deBoisblanc (New Orleans, LA, USA); J. Wirth (Portland, ME,
USA); S. Gaine (Baltimore, MD, USA); A. Waxman (Boston,
MA, USA); M. Rubenfire (Ann Arbor, MI, USA); M. McGoon
(Rochester, MN, USA); V. Tapson (Durham, NC, USA); R.
Schilz and A. Arroliga (Cleveland, OH, USA); J. Edleman
(Portland, OR, USA); S. Murali (Pittsburgh, PA, USA); N. Hill
(Providence, RI, USA); I. Robbins (Nashville, TN, USA); A.
Frost (Houston, TX, USA); F. Shardonofsky (Houston, TX,
USA); G. Elliott (Salt Lake City, UT, USA); D. Zwicke
(Milwaukee, WI, USA); A Keogh (Sydney, Australia); M.
Kneussl (Wein, Austria); M. Delcroix (Leuven, Belgium); D.
Langleben (Montreal, Canada); J. Granton (Toronto, Canada);
D. Ostrow (Vancouver, Canada); M. Hoeper (Hannover,
Germany); N. Berkman (Jerusalem, Israel); M. Kramer
1202
VOLUME 28 NUMBER 6
(Petach Tikvah, Israel); I. Ben-Dov (Tel-Hashomer, Israel); J.
Sandoval (Mexico City, Mexico); A. Boonstra Amsterdam, the
Netherlands); A. Torbicki (Warsaw, Poland); M. GomezSanchez (Madrid, Spain); J. Pepke-Zaba (Cambridge, UK); C.
Black, S. Gibbs and D. Kiely (London, UK); T. Higenbottam
(Sheffield, UK); A. Peacock (Glasgow, UK); P. Corris
(Newcastle-upon-Tyne, UK).
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